The molecular mechanisms that control cell growth in the heart are especially intriguing from both a biological and clinical point of view. Cardiac myocytes irreversibly lose the ability to divide soon after birth, contributing to the limited capacity to regenerate functional muscle mass after myocardial infarction. Conversely, cardiac myocytes can be provoked to undergo hypertrophy by a hemodynamic load; thus, increased work is transduced to increased mass. Cellular oncogenes have been postulated to function in a regulatory cascade for transduction of growth signals and to control movement through the cell cycle and initiation of DNA synthesis. However, very little is presently known about either expression or function of cellular oncogenes in cardiac muscle. The goal of this proposal is to elucidate, at the molecular level, fundamental mechanisms that control the relative ability of cardiac myocytes to replicate DNA and divide, by examining (i) the perinatal loss of proliferative capacity, and (ii) the hypertrophic response to pressure overload, in rat cardiac myocytes. These investigations are focused on the respective contributions of the myc and ras genes. First, the investigators will analyze the DNA synthesis induced by growth factors in vivo, in relation to basal and inducible expression of cellular oncogenes, during cardiac myocyte development. Second, the investigators will characterize DNA synthesis induced by pressure overload in vivo, in relation to basal and inducible oncogene expression, during later cardiac development. Third, the investigators will test whether exogenous oncogene alleles or the proteins they encode can function as a surrogates for growth factors that rat cardiac myocytes normally require for DNA synthesis, and can overcome the age-related block to DNA synthesis during cardiac muscle development. The biology of cardiac growth control differs in essential ways from both "senescence" in fibroblastic cells and "commitment" in skeletal muscle, and therefore its molecular basis cannot be readily extrapolated from data in other systems. Taken together the studies proposed here will test the hypothesis that cardiac growth control involves transduction of growth factors signals by ras and myc proteins, and will determine whether events proximal or distal can account for the loss of proliferative capacity during cardiac myocyte development.